Prognostic significance of promyelocytic leukemia expression in gastrointestinal stromal tumor; integrated proteomic and transcriptomic analysis.
Bottom Line: Among the 2555 genes analyzed, we found that promyelocytic leukemia (PML), a tumor suppressor gene, was significantly downregulated in I-GIST at both the protein and mRNA levels (P < 0.01; fold difference ≥2.0).Immunohistochemistry of 254 additional cases from multiple clinical facilities showed that PML-negative cases were significantly frequent in the I-GIST group (P < 0.001).The 5-year recurrence-free survival rate was significantly lower in the PML-negative than in the PML-positive cases (60.1% vs 91.7%; P < 0.001).
Affiliation: Division of Pharmacoproteomics, National Cancer Center Research Institute, Tokyo, Japan; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.Show MeSH
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Mentions: We validated the correlation of PML expression with the tumor site and patients' outcome using immunohistochemistry in 254 additional samples from the National Cancer Center Hospital (156 cases) and Niigata University Hospital (98 cases). PML immunostaining showed a nuclear speckled pattern or a diffuse nucleoplasmic pattern (Fig.2a–c). Vascular endothelial cells were strongly positive for PML expression, as described in a previous report.34 Among the 254 cases, 196 cases (77.2%) showed diffusely positive staining and were classified as PML-positive. The remaining 46 cases (18.1%) showing focal positivity and 12 cases (4.7%) that were negative were classified as PML-negative. Thirty-six of 211 cases with S-GIST (17.0%), 12 of 22 cases with I-GIST (54.5%) and 10 of 21 cases arising in other organs (47.6%) showed PML-negative, the differences being statistically significant (P < 0.001). Expression of PML was also correlated with tumor size (P < 0.001), mitosis (P < 0.001) and NIH consensus criteria (P < 0.001) as well as the tumor site (Table3). Kaplan–Meier survival analysis showed that the 5-year RFS rate was significantly lower for PML-negative than for PML-positive cases (60.1% vs 91.7%; P < 0.001) (Table3 and Fig.2d). Tumor site, histologic subtype, tumor size, mitosis and NIH consensus criteria were also significantly correlated with RFS in the univariate analysis. The correlation coefficient between NIH consensus criteria and tumor size was 0.78, and that between NIH consensus criteria and mitosis was 0.71 (Suppl. Table S9). They were especially high among those between other variables. Therefore, tumor size and mitosis were excluded from the variables entered into the Cox proportional hazards model to avoid multicollinearity. As a result, PML negativity was an independent unfavorable prognostic factor (hazard ratio [HR] = 2.739; P = 0.001) in addition to an indicator of a high-risk of recurrence according to the NIH consensus criteria (HR = 13.121; P < 0.001).
Affiliation: Division of Pharmacoproteomics, National Cancer Center Research Institute, Tokyo, Japan; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.